1. Field of the Invention
The present invention relates generally to the fields of gastric functions and dopamine receptor research. More specifically, the present invention relates to uses of dopamine 3 receptor agonists and antagonists in the treatment of gastrointestinal disorders.
2. Description of the Related Art
Gastrointestinal (GI) motility regulates the orderly movement of ingested material through the gut to ensure adequate absorption of nutrients, electrolytes and fluids. Appropriate transit through the esophagus, stomach, small intestine and colon depends on regional control of intraluminal pressure and several sphincters that regulate forward movement and prevent back-flow of gastrointestinal contents. The normal gastrointestinal motility pattern can be impaired by a variety of circumstances including disease and surgery.
Disorders of gastrointestinal motility can include, for example, gastroparesis and gastroesophageal reflux disease (GERD). Gastroparesis is characterized by delayed emptying of stomach contents. Symptoms of gastroparesis include stomach upset, heartburn, nausea and vomiting. Acute gastroparesis can be caused by drugs, viral enteritis and hyperglycemia. The most common underlying disease resulting in gastroparesis is diabetes.
Gastroesophageal reflux is a physical condition in which stomach contents (e.g., stomach acid) reflux or flow back from the stomach into the esophagus. Frequent reflux episodes (e.g., two or more times per week) can result in a more severe problem known as gastroesophageal reflux disease (GERD). The most common symptom of gastroesophageal reflux disease is a burning sensation or discomfort behind the breastbone or sternum and is referred to as dyspepsia or heartburn. Dyspepsia can also mimic the symptoms of myocardial infarction or severe angina pectoris. Other symptoms of gastroesophageal reflux disease disease include dysphagia, odynophagia, hemorrhage, water brash and respiratory manifestations such as asthma, recurrent pneumonia, chronic coughing, intermittent wheezing due to acid aspiration and/or stimulation of the vagus nerve, earache, hoarseness, laryngitis and pharyngitis.
Reflux episodes which result in gastroesophageal reflux disease, can occur both during the daytime (i.e., when the subject is in a waking state) and at nighttime (i.e., when the subject is in a non-waking state). Gastroesophageal reflux disease occurring at nighttime is commonly referred to as nocturnal gastroesophageal reflux disease. Nocturnal gastroesophageal reflux disease is distinct from daytime or diurnal gastroesophageal reflux disease not only in the timing of the reflux episode, but in the severity of the damage which occurs as a result of the reflux. More specifically, nocturnal gastroesophageal reflux disease can be particularly damaging to the pharynx and larynx and a strong association between nocturnal gastroesophageal reflux disease and asthma exists. The increased damage associated with nocturnal gastroesophageal reflux disease is due to a decrease in natural mechanisms which normally help protect against reflux (e.g., saliva production and swallowing), which occur when the patient is sleeping. This decrease leaves the esophagus more vulnerable to damage and can increase microaspiration. In addition, while asleep the body is in the recumbent position, eliminating the effect of gravity, which can clear gastric content from the esophagus. Sleep disorders are also associated with nocturnal gastroesophageal reflux disease resulting in daytime sleepiness and a significant decrease in the overall quality of life.
On a chronic basis, gastroesophageal reflux disease subjects the esophagus to ulcer formation or esophagitis and can result in more severe complications such as, esophageal erosion, esophageal obstruction, significant blood loss and perforation of the esophagus. Severe esophageal ulcerations occur in 20-30% of patients over age 65. In addition to esophageal erosion and ulceration, prolonged exposure of the esophageal mucosa to stomach acid can lead to a condition known as Barrett's Esophagus. Barrett's Esophagus is an esophageal disorder that is characterized by replacement of normal squamous epithelium with abnormal columnar epithelium. This change in tissue structure is clinically important not only as an indication of severe reflux, but as an indication of cancer.
Many factors are believed to contribute to the onset of GERD. A number of factors involve failure of the lower esophageal sphincter mechanism to work properly. The lower esophageal sphincter is tonically contracted to prevent reflux of gastric contents. In a healthy person the muscle relaxes only during swallowing to allow food to pass and also on average three to four times an hour in a phenomenon known as transient lower esophageal sphincter relaxations. In gastroesophageal reflux disease sufferers, the frequency of transient lower esophageal sphincter relaxations can be much higher, for example, as high as eight or more times an hour and weakness of the lower esophageal sphincter allows reflux to occur. Other factors that can contribute to gastroesophageal reflux disease include delayed stomach emptying and ineffective esophageal clearance. Delayed stomach emptying leads to reflux of the gastric contents into the esophagus.
Current methods to treat gastroesophageal reflux disease include lifestyle changes such as weight loss, avoidance of certain foods that exacerbate the symptoms of gastroesophageal reflux disease and avoidance of excessive bending. Elevation of the head of the bed helps reduce nocturnal reflux. While these avoidance strategies can be useful, the efficacy of lifestyle modification alone for the treatment of gastroesophageal reflux disease is not supported.
Medications for the treatment of gastroesophageal reflux disease include conventional antacids, for example, TUMS® and ROLAIDS® which provide only short term relief. H.sub.2 receptor antagonists, for example, nizatidine (AXID®), ranitidine (ZANTAC®), famotidine (PEPCID® and PEPCID COMPLETE®), roxatidine (ROTANE® or ZORPEX®) and cimetidine (TAGAMET®), are more effective in controlling gastroesophageal reflux disease, but do not treat the underlying disease. However, patients receiving H.sub.2 receptor antagonists develop tolerance to the drugs rendering the drugs ineffective in their ability to inhibit acid secretion.
More powerful secretory inhibitors, such as the proton pump inhibitors, for example, esomeprazole (NEXIM.RTM.), omeprazole (PRILOSEC.RTM. and RAPINEX.RTM.), lansoprazole (PREVACID.RTM.), rabeprazole (PARIET.RTM., ACIPHEX.RTM.) and pantoprazole (PROTONIX.RTM.) are more effective than the H.sub.2 receptor antagonists but are very expensive and their efficacy relies on inhibition of active proton pumps as stimulated by meals, thereby having little or no effect on the occurrence of nocturnal gastroesophageal reflux disease.
Prokinetic drugs are another type of drug used in the treatment of gastrointestional motility disorders. Prokinetic drugs act to stimulate gastrointestinal motility. Stimulation can occur by direct action on smooth muscle or by an action on the myenteric plexus. The motor functions of the gastrointestinal tract are expressions of a balance at the level of smooth muscle cells between inhibitory mechanisms mainly regulated by dopamine and stimulatory events mainly regulated through the release of acetylcholine. Therefore gastrointestinal motility can be stimulated by dopamine receptor 2 antagonists such as metoclopramide and domperidone, or by substances which release acetylcholine such as metoclopramide or the 5-HT.sub.4 receptor agonist, cisapride (PROPULSID.RTM.), or directly by cholinergic drugs which bind on muscarinic receptors of the smooth muscle cell such as bethanechol. Prokinetic drugs can both stimulate motility and coordinate the activity between different segments of the gastrointestinal tract. However, there are currently no prokinetic drugs available that are both effective and safe. For example, serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation have been reported in patients taking the prokinetic of choice, cisapride. As a result, strict limitations have been imposed on the prescribing of this drug. Further, the use of the dopamine antagonists, metoclopramide and domperidone, is associated with lack of patient tolerability, undesirable CNS effects, such as diskinesia and undesirable cardiovascular effects, such as QT prolongation.
Dopamine (DA) is present in large amounts in the gut and it regulates gastrointestinal (GI) function via inhibition of gastrointestinal motility. This is believed to be due to dopamine-induced suppression of acetylcholine release (a principal excitatory neurotransmitter in the gut) from enteric cholinergic neurons. Although dopamine is an important modulator of enteric function, much remains to be understood about its exact role in the gastrointestinal tract. Traditionally, dopamine has been thought to exert its effects via the D2 receptor (D2R) and hence antagonists of this receptor (metoclopramide and domperidone) are administered to alleviate symptoms associated with various gastrointestinal motility disorders.
The role of newly discovered dopamine receptors such as D3 and D4 in the regulation of gastrointestinal motility is not well known. Due to the side effects associated with current prokinetic drugs in the treatment of disorders related to gastrointestinal motility, it is important to develop newer drugs to manage such disorders. The presence of D3 and D4 dopamine receptors in the GI tract opens up new avenues for treating GI motility disorders that target these receptors.
The instant invention is directed to novel methods of treating GI motility disorders by targeting the dopamine 3 receptors in the GI tract. Prior art is deficient in the lack of useful agents to regulate gastrointestinal motility especially agents that target the dopamine 3 receptor. The present invention fulfills this long-standing need in the art.